FixpKa has a rule-based system to set the ionization state of input molecules. If pKa normalization is turned on, the molecule is set to its most energetically favorable ionization state for pH=7.4. The rule-based nature of this calculation allows it to be very fast. Further, despite being rule-based, this approach takes into account many secondary charge interactions.
While more advanced levels of theory can be found for predicting ionization states, this method is very well suited to virtual-screening database preparation. However, FixpKa may not be appropriate for hit-to-lead or lead optimization.